Kedjar, Y. | bioRxiv Science

bioRxiv2026

The Conformation of the Complementary Strand and the Deformation of the DNA Groove upon DDB2 Binding Justifies the Different Repair Rates for Cyclobutane Pyrimidine Dimers.

The repair of photo-induced DNA lesions through nucleotide excision repair machinery is still the source of important questions. It has been observed that the repair rate of the different cyclobutane pyrimidine dimers, i.e. the photoproducts induced by dimerization of two {pi}-stacked pyrimidines (T<>T, T<>C, C<>T, C<>C), depends on the nucleobases involved in the lesion. TT derivatives (T<>T) are removed more slowly than those containing cytosine, especially in 5. Using all-atom molecular dynamics simulations, we demonstrate that the variation of the repair rate observed in human skin and in cultured cutaneous cell may be associated to the recognition of the four lesions by the DDB2 protein moiety, and more specifically by the differential structural deformation induced on the complementary strand and the major groove. These effects may then hamper differentially the downstream recruitment of the repair complexes. The observed DNA deformation correlates with the experimental repair rate and suggests a structural rationale for the different repair rates of CPD by nucleotide excision repair machinery. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=186 SRC="FIGDIR/small/724087v2_ufig1.gif" ALT="Figure 1"> View larger version (63K): org.highwire.dtl.DTLVardef@1c02e6forg.highwire.dtl.DTLVardef@28b3c1org.highwire.dtl.DTLVardef@3143fborg.highwire.dtl.DTLVardef@664d48_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗

bioRxiv2024

Histone H3 as a redox switch in the nucleosome core particle: insights from molecular modeling

Histones post-translational modifications are major regulators of the chromatin dynamics. Understanding the structural signature of these marks in the nucleosome context is of major importance to unravel their mechanisms of action and open perspectives for the development of new therapies. In this work, we rely on multi-microseconds molecular dynamics simulations and advanced structural analysis to unravel the effect of two modifications of the histone H3: S-sulfenylation and S-nitrosylation. These oxidative modifications are known to target the cysteine 110 on the histone H3, but there their effect on the nucleosome dynamics. In this study, we show that in a nucleosome core particle, S-sulfenylation and S-nitrosylation exhibit different structural signatures, which suggests that they play a different function. While S-sulfenylation destabilizes DNA-histone communication at the dyad and could be linked to the promotion of nucleosome disassembly events, S-nitrosylation exhibits a mild effect on the nucleosome dynamics and might have a different function. Our results highlight the fine tune link between the chemical nature of histone core post-translational modifications and their impact on the nucleosomes large architecture. We provide new insights into the regulatory mechanisms of histone oxidative modifications, about which very little is known so far.

biophysics↗